The present invention relates to new hydantoin derivatives, a process for the preparation thereof and pharmaceutical compositions containing the derivatives as active ingredients, particularly remedies for treatment of diseases caused by stress.
In the current community of advanced civilization and technology, stress due to human, internal or external causes are increasing. We suffer from various complicated diseases caused by the stress. As the causes of stress, there may be mentioned physical stimuli such as cold, noise and high energy radiation, chemical stimuli such as deficiency in oxygen and chemicals (for example, ACTH and cortisone), biological stimuli such as bacteria and viruses and mental stimuli such as fear, anxiety and fretfulness. Many kinds of diseases are caused by the stress mainly in the autonomic nervous system.
It is well known that if those kinds of stress are not relieved properly by the protective controlling actions of the living body, and they become chronic or they are fixed, there arises secondary adaptation diseases such as hypertension, nephrosclerosis, rheumatism, gastric ulcer and duodenal ulcer.
Selye reported that as adaptation syndromes, the following phenomena arise:
1. hypertrophy of adrenal cortex, PA0 2. atrophy of thymus and lymphatic tissue, and PA0 3. bleeding from the inside wall of the stomach and intestines or ulcer thereof.
Various remedies for relieving the stress which causes the above mentioned diseases have been developed. However, those remedies have disadvantages. For example, meprobamate used as an anti-anxiety agent is accompanied with addiction to drugs to cause convulsion and disturbance of consciousness as abstinence symptoms. Diazepam and chlordiazepoxide have the same disadvantages. Therefore, removing a patient from use of those drugs is a medical problem.
An object of the present invention is to provide a remedy useful for the treatment of diseases caused by stress and free from harmful side-effects.
The compounds relating to the present invention are new hydantoin derivatives having the general formula (I): ##STR1## in which at least one of R.sub.1, R.sub.2, and R.sub.3 is a group other than hydrogen and R.sub.1, R.sub.2 and R.sub.3 which may be the same or different are hydrogen, halogen, carboxyl, sulfonic acid, alkyl, hydroxyalkyl, haloalkyl or a group of formula OR.sub.7 in which R.sub.7 is hydrogen, saturated or unsaturated straight chain or branched aliphatic hydrocarbon, aralkyl or alkali metal atom, and X is alkyl, heterocyclic or a group of general formula (II): ##STR2## in which R.sub.4, R.sub.5 and R.sub.6 which may be the same or different are hydrogen, halogen, carboxyl, sulfonic acid, alkyl, hydroxyalkyl, haloalkyl or a group of formula OR.sub.7 (R.sub.7 having the same meaning as above).
Among the hydantoin compounds having one or two substituents at the 5-position, 5-ethyl-5-phenylhydantoin, 5,5-diphenylhydantoin (DPH), etc. have been known as anticonvulsants. Particularly, those compounds are used as anti-epilepsy drugs.
After intensive investigations on various hydantoin compounds having substituents at the 5-position, we have found that some 5,5-disubstituted hydantoin compounds having at least one substituted phenyl group at the 5-position have pharmacological effects remarkably effective against diseases caused by stress, particularly, sedative, analgesic, antiulcerogenic, sleep prolongation and antihypertensive effects. It has also been found that the compounds of the present invention act as a sedative on the central nervous system in contrast with DPH which stimulates the central nervous system as anticonvulsants, and the former compounds have pharmacological effects utterly different from those of DPH as will be understood by a study of the pharmacological tests given below.
An object of the present invention is to provide new hydantoin derivatives useful as a remedy for diseases caused by stress.
Another object of the present invention is to provide a process for preparing said derivatives from ketone.
Still another object of the invention is to provide medical compositions comprising said derivatives and at least one pharmaceutically acceptable carrier or diluent.